Comparison of Kaplan-Meier curves for probabilities of patients being in a wheelchair-bound state (A), being in a bedridden state (B), and dying (C) between patients with cerebellar type multiple system atrophy (MSA-C) and those with parkinsonian type MSA (MSA-P). Triangles and circles represent censored data indicating subjects with MSA-C and MSA-P, respectively. No significant differences in these variables were seen between the 2 groups (P = .47, P = .12, and P = .86 in A, B, and C, respectively).

Comparison of Kaplan-Meier curves for probabilities of patients being in a wheelchair-bound state (A), being in a bedridden state (B), and dying (C) between patients who developed autonomic dysfunction within 2.5 years after the onset of multiple system atrophy (group A) and others (group B). Triangles and circles represent censored data indicating subjects of groups A and B, respectively. Significant differences in these variables were seen between the 2 groups (P<.001, P<.001, and P = .02 in A, B, and C, respectively).

BackgroundMultiple system atrophy (MSA) is diverse in clinical phenotype, disease progression, and prognosis. Sudden death is a leading cause of death in patients with MSA.

ObjectiveTo determine what clinical factors affect the progression and survival prognosis of those with MSA.

DesignA retrospective review of the medical records of 49 consecutive Japanese patients with pathologically confirmed MSA (29 men and 20 women; mean ± SD age at onset, 59.8 ± 6.5 years). Cox proportional hazards models were used to compare the risks of being in a wheelchair-bound state, being in a bedridden state, and having a shorter survival.

ResultsThirty-one patients were diagnosed as having cerebellar type MSA, and 18 were diagnosed as having parkinsonian type MSA. Twenty-nine patients with cerebellar type MSA and 17 patients with parkinsonian type MSA had autonomic dysfunction. The median times from disease onset to being in a wheelchair-bound state, being in a bedridden state, death, and the development of autonomic dysfunction were 3.5, 5.0, 7.0, and 2.5 years, respectively. Patients with an early development of autonomic dysfunction (within 2.5 years from the onset of MSA) had significantly higher risks of being in a wheelchair-bound state (multivariate-adjusted hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.04-9.15), being in a bedridden state (HR, 3.87; 95% CI, 1.77-8.48), having a shorter survival (HR, 3.40; 95% CI, 1.61-7.15), and sudden death (HR, 7.22; 95% CI, 1.49-35.07).

ConclusionThe early development of autonomic dysfunction is an independent predictive factor for rapid disease progression and shorter survival in patients with MSA.

Multiple system atrophy (MSA) is a neurodegenerative disorder involving the extrapyramidal system, cerebellum, and autonomic nervous system, with glial cytoplasmic inclusions as a pathological hallmark.1,2 Based on the most prominent neurological symptoms, including ataxia, parkinsonism, and autonomic dysfunction, MSA involves the following neurodegenerative disorders: olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome.3 Recently, MSA has been classified into 2 clinical subtypes, cerebellar type (MSA-C) and parkinsonian type (MSA-P).4

Several predictive factors for the progression and survival prognosis of those with MSA have been proposed. Patients with MSA-P show a more rapid disease progression and survive for a shorter time than patients with MSA-C.5,6 Furthermore, the early development of motor and autonomic dysfunctions results in poor prognosis.6 Nocturnal and daytime stridors also have been considered a poor prognostic feature.7 However, the importance of these predictive factors remains controversial.

Because the sensitivity of the clinical diagnostic criteria for MSA without pathological findings has been relatively low,8 the study of the predictive factors for disease progression and survival prognosis is difficult. Therefore, we investigated the clinical features of 49 consecutive patients with pathologically confirmed MSA in 1 institute to determine predictive factors for disease progression and survival prognosis. In particular, we determined whether the early development of autonomic dysfunction indicates the rapid progression and shorter survival in patients with MSA.

METHODS

PATIENTS

We reviewed the medical records of patients referred to the Department of Pathology, Brain Research Institute, Niigata University, between January 1, 1970, and December 31, 2002. We recruited 49 consecutive patients with pathologically confirmed MSA according to a consensus statement on the diagnosis of MSA (definite MSA).4

CLINICAL ASSESSMENT

The onset was defined as the time patients first noted motor or autonomic symptoms: orthostatic hypotension, postural syncope, or urinary incontinence. The clinical features of the 49 patients were assessed and classified into 2 clinical phenotypes, MSA-C and MSA-P, based on the predominant motor dysfunction.4 The clinical assessment of autonomic involvement was conducted using 1 of the following 3 criteria: (1) orthostatic decrease in blood pressure within 3 minutes (by at least 30 mm Hg systolic or 15 mm Hg diastolic),4 (2) recurrent postural syncope (≥3 times),9 or (3) urinary incontinence.4 The evaluations of autonomic and motor disturbance were performed at the first hospital visit and at every subsequent visit, approximately once a month, by interviews and neurological examinations. The defined features of autonomic involvement were orthostatic hypotension for 15 patients, recurrent postural syncope for 6 patients, and urinary incontinence for 16 patients. Nine patients showed orthostatic hypotension and urinary incontinence simultaneously. The times from disease onset to being in a wheelchair-bound state, being in a bedridden state, death, and sudden death were assessed. For the survival analysis using Kaplan-Meier plots, 12 patients were censored on the date they required tracheotomy to prevent aspiration pneumonia and obstructive respiratory problems. None of these patients required continuous mechanical ventilator support for more than 1 month.

STATISTICAL ANALYSES

Data were analyzed using a commercially available software program (SPSS, version 11.5; SPSS Inc, Chicago, Ill). The frequency of clinical features was analyzed with a χ2 or Fisher exact test. Disease progression or survival was analyzed using Kaplan-Meier plots and a log-rank test between subgroups. Cox proportional hazards models were used to calculate multivariate-adjusted hazard ratios with 95% confidence intervals. In these models, the age at onset was entered as 1 of 2 categorical variables (<60 or ≥60 years old). P<.05 was considered statistically significant.

RESULTS

DEMOGRAPHICS AND CLINICAL FEATURES

The demographics and clinical features of the patients are presented in Table 1. Cerebellar type MSA was more frequent than MSA-P. There was no significant difference in the age at onset or in sex between those with MSA-C and those with MSA-P. The frequencies of limb ataxia, rigidity, tremor, and dysphagia significantly differed between these clinical subtypes. Twenty-nine patients with MSA-C and 17 patients with MSA-P showed autonomic dysfunction during the illness. The frequencies of the other motor symptoms (parkinsonism in those with MSA-C and cerebellar ataxia in those with MSA-P) were lower than that of autonomic dysfunction.

The patterns of disease progression were categorized into 14 groups in terms of the order of the onset of the following 3 major clinical features: cerebellar dysfunction, parkinsonism, and autonomic dysfunction (Table 2). The median times to develop autonomic dysfunction from the onset of MSA were 2.5 years in those with MSA-C and 2.0 years in those with MSA-P; however, the median times to develop a second motor symptom were 5.0 years in those with MSA-C and 4.5 years in those with MSA-P. Thus, the development of autonomic dysfunction preceded the development of a second motor symptom in 28 (90%) of the 31 patients with MSA-C and in 15 (83%) of the 18 patients with MSA-P.

PROGNOSIS AND CLINICAL FEATURES

The median times from the onset of MSA to being in a wheelchair-bound state, being in a bedridden state, and death were 3.5, 5.0, and 7.0 years (ranges, 1-11, 1-12, and 1-13 years), respectively. There was no difference in these variables between the patients with MSA-C and those with MSA-P (Figure 1). Sudden death was the second leading cause of death in the patients with MSA-C (7 patients [23%]) and a leading cause of death in the patients with MSA-P (6 patients [33%]). Another major cause of death in both groups was pneumonia, found in 9 (29%) of the patients with MSA-C and in 4 (22%) of the patients with MSA-P.

We then determined whether the early development of autonomic dysfunction affects disease progression. Because the median time to develop autonomic dysfunction from the onset of MSA was 2.5 years in the patients with MSA, we divided the 46 patients into 2 groups in terms of the onset time of autonomic dysfunction: group A (n = 26), within 2.5 years from the onset of MSA; and group B (n = 20), others. Three patients (2 with and 1 without autonomic dysfunction) who died within 2.5 years after the onset were excluded. In group A, the median times from the onset of MSA to being in a wheelchair-bound state, being in a bedridden state, and death were 2.5, 3.5, and 5.5 years, respectively. In contrast, in group B, they were significantly delayed (5.5, 6.0, and 9.5 years, respectively) (P<.001, P<.001, and P = .02, respectively) (Figure 2). The risk of being in a wheelchair-bound or a bedridden state was assessed using the Cox proportional hazards model adjusted for clinical subtype, sex, age at onset, and the development of autonomic dysfunction within 2.5 years after the onset of MSA or later (Table 3). Among the patients who developed autonomic dysfunction within 2.5 years after the onset of MSA, the hazard ratio for being in a wheelchair-bound state was 4.32; and for being in a bedridden state, 3.87.

The risk of shorter survival or sudden death was assessed using the Cox proportional hazards model adjusted for clinical subtype, sex, age at onset, the presence of stridor, tracheotomy, and the development of autonomic dysfunction within 2.5 years after the onset of MSA. Among the patients who developed autonomic dysfunction within 2.5 years after the onset of MSA, the hazard ratio for shorter survival was 3.40; and for sudden death, 7.22. On the other hand, clinical subtype, sex, the age at onset, and the presence of stridor had no significant effect on the survival time or the risk of sudden death. Tracheotomy significantly decreased the risks of shorter survival and sudden death (Table 3).

COMMENT

This study shows that the early development of autonomic dysfunction is an independent risk factor for rapid disease progression and shorter survival in patients with MSA. Our findings are in good agreement with those of a previous report by Watanabe et al,6 which reported that the time from an initial symptom to combined motor and autonomic dysfunction is a predictive factor for poor prognosis and shorter survival in patients with MSA. Furthermore, we showed that the early development of autonomic dysfunction increases the risks of shorter survival and sudden death even after adjustment for the presence of tracheotomy or stridor, which is a hallmark of obstructive respiratory problems in patients with MSA, whereas an obstructive respiratory problem has been considered as a factor for poor prognosis.7 In contrast to the findings of previous studies,5,6,9,10 clinical phenotype, sex, and age at onset had no effects on disease progression or shorter survival in this study. The main limitations of this study are the nature of the retrospectively collected data and the use of data from autopsy cases, which are likely to be biased toward more severe cases, resulting in an artifactual lowering of survival time. However, the strength of our study lies in its design, including consecutive patients with pathologically confirmed MSA collected from a single institute. This might explain the difference in our results from those of previous studies.

The pathophysiological mechanism of the poor prognosis of MSA associated with autonomic nervous system involvement is not clear. Although the loss of preganglionic sympathetic neurons in the intermediolateral cell column has been found to correlate with the presence of autonomic dysfunction,11 the loss of catecholaminergic neurons in the rostral ventrolateral medulla may also contribute to sympathetic vasomotor failure in those with MSA.12 Furthermore, there is severe serotoninergic neuron loss in the nucleus raphe magnus, raphe obscurus, raphe pallidus, and ventrolateral medulla in patients with MSA.13 The medullary serotoninergic system controls autonomic and respiratory functions. Neuron loss in this system has been observed with sudden infant death syndrome in some patients,14 suggesting that neuron loss in the system contributes to autonomic dysfunction, central hypoventilation, and sudden death in patients with MSA. Endeavors to find a pathological substrate for autonomic dysfunction that causes sudden death in patients with MSA are needed.

Another interesting finding in this study is that the frequency of MSA-C was 1.5-fold higher than that of MSA-P. This result is in good agreement with that of a previous study6 in which Japanese patients with definite or probable MSA were analyzed. By contrast, in the Caucasian population, the frequency of MSA-P is 1.5- to 4.0-fold higher than that of MSA-C.3,9,10,15 This difference could be caused by genetic or environmental factors in these populations.

In summary, we found that the early development of autonomic dysfunction is a predictive factor for rapid disease progression and shorter survival in patients with MSA. Although the classification of MSA as MSA-C and MSA-P well represents the motor symptoms, it does not predict disease progression or survival prognosis. The term Shy-Drager syndrome, which has been used to describe patients with MSA with prominent autonomic dysfunction, is less frequently used in recent MSA studies.4 However, the classification of patients depending on autonomic nervous system involvement will be useful for predicting disease progression or survival prognosis and planning a therapeutic trial for MSA.

Funding/Support: This study was supported in part by grants for Surveys and Research on Specific Diseases and Ataxias and Neurodegenerative Diseases from the Ministry of Health, Labor, and Welfare of Japan.

Acknowledgment: We thank the patients and their families for their participation in the study.